The complement system is a key component of innate immunity. It is found in the blood of mammals and is composed of over 25 proteins that recognize antibodies (immune complexes) and various pathogen surfaces which trigger a cascade of events aimed at protecting the host from “foreign” treats. During the complement activation cascade, a small peptide of 74 amino acids named C5a, is produced. This peptide has a number of biological activities including: 1) increases the permeability of small blood vessels, 2) induces the contraction of smooth muscles, 3) attracts and stimulates the pro-inflammatory activity of a variety of immune cells like macrophages, neutrophils and mast cells (reviewed by Kohl in Molecular Immunology (2001), 38:175-187). C5a mediates these effects through a G-protein coupled receptor named C5aR.
Excessive or uncontrolled complement activation can sometimes injure the host. The production of C5a is implicated in the pathogenesis of a variety of inflammatory conditions such as rheumatoid arthritis, systemic lupus erythematosus, glomerulonephritis, ischemic heart diseases, reperfusion injury, sepsis, psoriasis, atherosclerosis, inflammatory bowel diseases (IBD), adult respiratory distress syndrome (ARDS), asthma, COPD and Alzheimer's disease (reviewed by Mizuno and Morgan in Curr Drug Targets Inflamm Allergy (2004) 3:87-96 and by Kohl in Molecular Immunology (2001), 38:175-187).
Agents blocking the interaction of C5a with its receptor would be useful for treating the various inflammatory disorders driven by complement activation.